This application is a supplement to a recently funded randomized controlled trial, Phytoestrogens in Progression of Atherosclerosis (U01-AT001653). This supplement is focused on isoflavone (iso)-rich soy protein supplementation and breast cancer risk in postmenopausal women. Evidence from observational studies indicates that soy intake may reduce breast cancer risk. If beneficial effects of soy can be demonstrated in a randomized controlled trial using mammographic percent density (MPD), an established marker of breast cancer risk, this will considerably strengthen the results obtained from observational studies. Design, duration and size of the parent trial make it an ideal platform upon which to adequately assess the effects of iso-rich soy protein supplementation on breast cancer risk. Since the central portion of the trial has been funded, a very robust database will be obtained at considerable savings. The objective of this supplement is to investigate the effect of iso-rich soy protein supplementation on breast cancer risk in 300 healthy postmenopausal women in a randomized, double-blind, placebo-controlled, 2.5 year trial. The primary Specific Aims are to study the effects of iso-rich soy protein supplementation on MPD and circulating female sex hormone levels (estrogen, progesterone, prolactin, sex hormone binding globulin [SHBG]). Specifically, changes in MPD and circulating hormone levels will be compared between treatment groups (Specific Aims 1 and 2). There are several inter-related secondary objectives designed to investigate potential individual differences in response to supplementation. Among women randomized to the soy arm (n=150), we will determine whether blood isoflavone levels predict changes in MPD (Specific Aim 3) and circulating hormone levels (Specific Aim 4). We will determine whether changes in MPD (Specific Aim 6) and circulating hormone levels (Specific Aim 7) are influenced by polymorphisms in selected genes involved with estrogen and progesterone synthesis and metabolism that are thought to be affected by soy isoflavones. We will determine whether changes in blood hormone levels predict changes in MPD among women randomized to the soy arm (Specific Aim 5). Finally, using baseline measurements of all subjects (n=300), we will determine the relationship between MPD and circulating sex hormone levels (Specific Aim 8). [unreadable] [unreadable] [unreadable]